Substituted polyhydrobenz [cd] indoles and process for their preparation



Unite SUBSTITUTED POLYHYDROBENZ [CD] INDULES AND PROCESS FOR THEIR PREPARATION 32 Claims. (Cl. 260-319) This invention relates to novel organic compounds and more particularly to substituted l,2,2a,3,4,5-hexahydrobenz[cd]indoles and the process for their preparation.

The bases of the substituted polyhydrobenz[cd]indoles of this invention are represented by the formula CH3 CH2 R2 OH N-Ri wherein R represents a radical of the group consisting of aliphatic radicals having from one to eight carbon atoms, monocarbocyolic aromatic, and monocarbocyclic arematic-substituted lower alkyl radicals; R1 represents an alkyl radical having from one to eight carbon atoms; R2 represents a lower acyloxymethyl or hydroxymethyl radi= cal; R3 and R4 each represents a lower alkyl radical, and when taken together, R3 and R4 represent a polymethylene chain having from two to three carbon atoms.

Broadly speaking, this invention also comprehends cer-' tain substituted polyhydrobenz[cd]indoles which are in termediates "in preparation of the above compounds. These intermediate compounds can be prepared by epoxi dation of correspondingly substituted 1,2,2a,3-tetrahydrobenz[cd]indoles. The epoxidation can be conveniently eiiected by means of per-acids, such as perbenzoic acid, monoperphthalic acid, peracetic acid and the life.

The substituted polyhydrobenz[cd]indoles according to the above formula are useful intermediates in the preparation of lysergic acid. Thus, they can be converted to the correspondingly substituted 5-keto-4-(N-alkyl-N- aceton-yl) amino 1,2,2a,3,4,5 hexahydrobenz[cd]- indole ketals, from which, by following the process of copending application Serial No. 458,674, there is obtained lysergic acid. As is known to the art, lysergic acid can be converted to certain ergot alkaloids which are useful oxytocics.

The following series of equations, wherein R has the same significance as hereinabove and alk represents a lower alkyl radical, illustrates the preparation of certain of the new substitued N-acyl-polyhydrobenz[cd]indoles and intermediates thereof, and their conversion to l-acyl- 5- keto 4 (N alkyl N acetonyl) amino- 1,2,2a,3,4,5 hexahydrozenz[cd]indole ethylene ketal. The starting material for the reactions is an 'N-acyl-5 formyl l,2,2a,3-tetrahydrobenz[cd]indole, the prepara= ice 2 tion and properties of which are described in S. Patent No. 2,663,714.

Hydrogen peroxide perbenzole acid RC O-N II III I CHr-CH: k-C ho (EH20 (30-2111: 1 on, on,

iINbia cnF- fig 8 I 0 ac 0N Iv CH: C perbenzolc acid alk-(C112 o Referring to the equations, it will be seen that N'- acyl i s formyl l,2,2a,3 -tetrahydrobeiii[cd]indole (1 is converted to the corresponding N-acyl-5-hydroxynietliyi 1,2,2a,3-tetrahydrobenz[cd]indole (H) which upon treatment with perbenroic acid forms the eeries'pondmg epoxy derivative (III). Compound ll upon treatment like.

with an acylating agent, such as an acid anhydride, forms the corresponding S-acylbxymethyl compound (IV), which upon treatment with perbenzoic acid forms the corresponding N -acyl 4,5 epoxy 5. acyloxymethyl- 1,2,2a,3,4, 5-hexahydrobenz[cd]indole (V): (Compound III, when reacted with an alkylaminoacetone ketal, herein exemplified; by methylaminoacetone ethylene ketal, forms an N-acyl-4-(N-methyl-N-acetonyl)-amino-5-hydroxy 5- hydroxymethyl 1,2,2a,3,4,5 hexahydrobenz- [cd]indole ethylene ketal (VII), which upon treatment with periodic acid forms an N-acyl-4-(N-methyl-N- acetonyl) amino 5 keto 1,2,2a,3,4,5 hexahydrobenz[cd]indole'ethylene ketal (VIII). Likewis eycompound V is converted by treatment with methylaminoacetone e thylene ketal to an N-acyl-4-(N-methy-l-N- acetonyl) amino 5 hydroxy 5 acyloxymethyll,2,2a,3,4,5 hexahydrobenz[cd]indole ethylene ketal 4.- amide. To the mixture were added 4.5 g. (0.014 mol) of pyridine hydrobromide perbromide. The mixture was warmed to 60 and was then allowed to stand at room temperature for three and one half hours. To it was added a previously prepared solution of 4.2 g. of semicarbazide hydrochloride and 3.6 g. (0.042 mol) of anhydrous sodium acetate in 35 ml. of dimethyl form.- amide, and the mixture was heatedon a steam bath for one hour. The dimethylformamide was evaporated in'vacuo, the dark syrupy residue was treated-with water, and the amorphous product which separated was filtered, and washed well with water. The precipitate was dissolved in a minimum ofhot glacial acetic acid, the solu- (VI), which on hydrolysis and oxidation-forms an N- acyl 4 (N methyl N acetonyl) amino 5 keto- 1,2,2a,3,4,5 hexahydrozenz [c'd]indole ethylene ketal (VIII).

Alternatively, Compound I can be epoxidizedby treatment withalkaline hydrogen peroxide to form" an N- I acyl-5-forrnyl-.4, 5 -epoxy-l,2,2a,3,4,5- hexahydrobenzlcdl indole, which..,on reduction with sodium borohydride afiords Compound III. Other variations in the course of the processes disclosed herein willbeapparent to the art, such as combination of successive reaction steps where by-p'roducts of reaction are-eliminated or are non-interfering with succeeding manipulations, and the This invention is further illustrated by the following examples. I

' I EXAMPLE 1 Preparation of 1-benz0yl-4,5-ep0xy-5-f0rmyl- I 1,2,2a,3,4,5-hexahydrobenz[cd]indole 32.4 g. (0.83 gram atom) of potassium were dissolved in a mixture of 800 ml. of dry tertiary butanol and 700 ml. of dry benzene maintained under nitrogen. The solvents were removed in vacuo, and the potassium t-butoxide was suspended in 1500 ml. of a mixture of equal volumes of dry benzene and dry toluene. The mixture was maintained under an atmosphere of nitrogen, and cooled in an ice bath. and to it were added 136 g. (0.49 mol) of l-benzoyl-S-keto-l,2,2a,3,4,5= hexahydrobenz[cd]indole prepared according to the procedure ofUfS. Patent No. 2,663,714. To the mixture, while being cooled in the ice bath, 106g.- (0.86mol) of ethyl -chloroacetate were added dropwise, with stirring over a period of ten minutes. The cold solution was stirred for fifteen minutes, and finally was heated and refluxed for fifteen minutes. The mixture was cooled rapidly and treated with afew hundred grams of ice. The aqueous layer was separated, and the organic layer was washed successively withl liter of water, 1 liter of 1.5 N sulfuric acid, 1 liter of 0.7 N sulfuric acid, 1 liter of water and 1 liter of saturated sodium bicarbonate solution. The solution was dried over anhydrous magnesium sulfate, and the solvents were evaporated in vacuo. The syrupy glycidic ester remaining was dissolved in 1200 ml. of absolute ethanol, and to the solution were added slowly with shaking m1. of 50 percent sodium hydroxide solution. The mixture was allowed to stand for twenty minutes after which it was heated rapidly to -75 and held there for five minutes, and then cooled for about one hour. The

tion was treated with decolorizing carbon, and diluted with two volumes of methanol. After chilling to about 5 C. for a few hours a crystalline precipitate of the semicarbazone of l-benzoyl-S-formyl-l,2,2a,3-tetrahydrobenzicdlindole separated. The precipitate was. filtcred off and washed with small amounts of methanol and. ether. Thesemicarba zone .of l-be nz oyl-5-formyll,2,2a,3-tetrahydrobenz[cd]indole melted with decomposition at about 232-233" C.

22.9 g. of the semicarbazone of l-benzoyl-S-formyll,2,2a,3-tetrahydrobenz[cd]indole were mixed with 160 g. of redistilled pyruvic acid, 230 ml. of chloroform and 10 ml. of water. The solution was shaken until homogeneous and allowed to stand overnight. It was diluted with 200 ml. of chloroform and washed with three 300 ml. portions of water and with two 300 ml. portions of saturated sodium bicarbonate solution. The chloroform solution was dried'over anhydrous magnesium sulfate, treated with decolorizing carbon, and concentrated to dryness in vacuo. The crystalline residue of 1- benzoyl-S-formyl-l,2,2a,3-tetrahydrobenz[cd]indole was digested with ml. of hot ethanol, cooled, filtered, and washed with methanol and ether. The yield was 16.1 g., 65 percent of theory. It melted at about 171- 174 C. After recrystallization of a sample from ethanol, it melted at about 177178 C. V v

A solution of 43.2 g. of l-bnzoyl- S-for'rnyl-1,2,2a,3- tetrahydrobenzEcdlindole in 5.6 liters of methanol'was cooledto about 5 C. To the cooled solution were added slowly and with stirring 530 ml. of previously cooled 30 percent hydrogen peroxide, with stirring and continued cooling in ice. fter all of the hydrogen peroxide had been added, 77- ml. of 5 percent aqueous sodium carbonate solution was "added, after which stirring was continued for about six'hour. To the reaction mixture were then added 6 liters of cold water followed by 4.5 ml. of glacial acetic acid. The reaction mixture was'redu'c'e'd to-about one half its 'volume by evaporation'of the alcohol in vacuo, and to the concentrated solution distilled water was added slowly and with stirring, until the solution became cloudy. The reaction mixture was cooled overnight and the precipitate which resulted, comprising l-benzoyl- 5-formyl-4,5-epoxy-1,2,2a, 3,4,5-hexahydrobenzEcd]indole, was removed by filtration and crystallized from methanol. 7

l-benzoyl-S-fo'rmyl-4,S-epoxy-1,2,2a,3,4,5 hexahydrobenzicdlindole thus prepared melted with decomposition at about -143 C; After recrystallization from wet methanol the product in the form of its monohydrate melted decomposition at about -147f C. V

sodium salt of 1-benzoyl-5-carboxymethyl-S, cc-cpoxy- 3 1,2,2a,3,4,5-hexahydrobenz[cd]indole which separated wasfiltered off, washed with methanol and ether, and dried. The salt melted with decomposition at about 220-223" C. i I 5 g. (0.014 mol) of the sodium salt of 1-benzoyl-5- carboxymethyl-5,m -epoxy 1,2,2a,3,4,5 hexahydrobenz- [cdllindole was mixed with 100 ml. of dimethylform- EXAMPLE 2 Preparation of 1-benz0yl-4,5-epoxy-5-hydroxynterhyl- 1,2,2a,3,4,5-hexahydrobenz [pd] indole reener hour's. Eight hundred ml. of water were addedtc the reaction mixture, whereupon a precipitate of l-behz'ioylhydroxymethyl 1,2,2a,3 tetrahydrobenz[cd]indole formed. It was removed by filtration and washed with acetone. l-benzoyl-5-hydroxymethyl-1,2,2a,3-tetrahydrobenz[cd]indole monohyd'rate thus prepared melted with decomposition at about 108-ll0 C.

To a solution of 3.5 g. of perbenzoic acid in 70 ml. of cold chloroform were added 6 g. of l-benzoyl-S-hydroxymethyl-1,2,2a,3-tetrahydrobenz[cdlindole The resulting solution was allowed to stand in a refrigerator for about seventeen hours, and then was washed with two 30 ml. portions of saturated aqueous sodium bicarbonate solution. The washed chloroform solution was dried over anhydrous magnesium sulfate, and evaporated to dryness vacuo. The residue was crystallized from methanol. The 1-benzoyl-4,5-epoxy-5-hydroxymethyl 1,2,2a,3,4,5- hexahydrobenzkdliridole thus prepared melted at about 175-176 C. p

Other l acyl derivatives of 5-formyl-l,2,2a,3-tetrahydroben'z[cd]indole can be employed in the reduction .procedure of this example to yield the corresponding l-acyl- S-h'ydro'xymethYl l,2,2a,3 tetrahydrobenz[cd]indoles. Thus for example, in place of the l-benzoyl derivatives, l-propionyl, l-caproyl, l-n-heptanoyl, l-acetyl, l-phenylacetyl and the like acyl derivatives of 5-formyl1,2,2a,3- tetrahydrobenz[cd]indole can be reduced to form the corresponding l-propionyl, l-caproyl, l-heptanoyl, l-ace- 'tyl, and l-phenylacetyl5-hydroxymethyl-l,2,2a,3tetrahydrobenzEcdJindoles, respectively. Instead of the sodium borohydride employed for reduction in the procedil're of this example, other mild hydrogenating agents can be used, as for exam le, Zinc 811d acids, lithiiltn borohydride, hydrogen with catalyst such as palladium black and the like.

The reduction can be effected at temperatures ranging from about room temperature to 150 C., or higher, but the formation of undesirable by-products increases rapidly at higher temperatures. p

The l-acyl-S-hydroxymethylpolyhydrobenz[cd]indoles can be epoxidized by means of any per-acid, such as peracetic acid, monoperphthalate acid, and the like.

EXAMPLE 3 Preparation of methylaminoacetone ethylene kezal A mixture of 1200 ml. of liquid methylamine and 300 g. of chloroacetone ethylene ketal was heated in a high pressure autoclave at 160-465" C. for about twenty-five hours. The reaction mixture was cooled and the excess methylamine was evaporated. The residue, comprising methylaminoacetone ethylene ketal, was dissolved in several volumes of ether. The ether solution was mixed with a solution of 130 g. of potassium hydroxide in 65 ml. of water, and was decanted from the sludge. extract containing methylaminoacetone ethylene ketal formed in the reaction was dried over solid potassium hydroxide, the ether was removed by evaporation, and the residue was distilled. The portion boiling at 158- 161 C. was collected, was dissolved in two liters of dry ether, and dry hydrogen chloride gas was passed into the solution until precipitation of the hydrochloric acid addition salt of the base was complete. The methylaminoacetone ethylene ketal hydrochloride thus prepared melted at about l65l67 C. It can be represented by the formula The methylaminoacetone ethylene ketal hydrochloride wassuspended in 1 liter of dry ether, and to the mixture was added with stirring a solution of 110 g. of potassium hydroxide in 55 ml. of water. Sufi'icient excess solid potassium hydroxide. was added to remove all water, and the organic layer was decanted, and the ether was evaporated. The residue was distilled yielding'methylaminoactoneethyl'ene ketal which' boiled atabo'u't 158-159 C..

use in the process ofthe invention as exemplified by the following example. Likewise, aminoacetone dialkyl lzetals, wherein the amino group can be substituted with an alkyl radical having from one to eight carbon atoms,

. such as methylaminoacetone diethyl ketal, isopropyl- The ethereal arh'ihoacetone diethyl ketal, amylaminoacetone diethyl ketal, n-heptylaminoacetone dipropyl ketal and the like, cah be used in the procedure of the following examples to produce the corresponding l-benzoyl-5-keto-4-(N- alkyl-N-acetonyl') amino 1,2,2a,3,4,5 hexahydrobenz- [cdlindo'le 'dialkyl ketals.

EXAMPLE 4' Prepararibn Of 1 benzoyl-5-hydr0xy-5 hydr0xymethyl-4- -(N me'tfiyl-N-aeetonyl)-amin0-1,2,2a,3,4,5-hexahydr0- benzlcdlindole ethylene ket'al A mixture of 12 g; of 1-benzoyl-4,S-epoxy-S-hydroxymethyl-1,2,2a,3,4,5-hexahydrobenz[cd]indole and 50 ml. of methylaminoacetone ethylene ketal was heated under nitrogen in an oil bath at about C. for about sixteen hours. The excess amino ketal was removed by distillation in vacuo, and the residue was taken up in the minimum amount of benzene. By addition of petroleum ether to the benzene solution, a gummy precipitate of l-benzoyl- 5-liydroxy-5-hydroxymethyl-4-(N-methyl-N acetonyl) amino-l,2,2zt,3,4,5, hexahydrobenzlcdlindole ethylene ketal was formed. The supernatant liquid was removed by decantation, and the gum was dissolved in 25 ml. of chloroform. The chloroform solution was washed with three 25 ml. portions of cold dilute hydrochloric acid to remove all of the basic material. The combined acid extracts were neutralized by the addition of sodium bicarbonate, and the neutral aqueous solution was extracted with three 50 ml. portions of chloroform. The combined chloroform extracts were dried over anhydrous magnesium sulfate, and the chloroform was removed by evaporation in vacuo. The residue was crystallized from ethyl acetate. Y

i-Benzoyl-5-hydroxy-5-hodroxymethyl-4-(N methyl N-acetony-l amino l,2,2a,3,4,5 hexahydrobenzEcd] indole ethylene lretal thus prepared melted at about 148- 150 C.

By using l-benzoyl-S-acetoxyniethyl-4,5, epoxy-l,2,2a,- 4,5-hexyhydrobenzEcdJindole as a starting material in procedure of this example, there is obtained l-benzoyl- -hydroxy-5-acetoxymethyl-4-(N-methyl-N acetonyl) amino-l,2,2a,3,4,5, hexahydrobenzlcdlindole ethylene ltetal melting at about -132" C.

A solution consisting of 1 g. of 1-benzoyl-5-hydroxy 5- hydroxymethyl 4 (N-methyl-N-acetonyl)=amino-l,2,2a, 3,4,5,-hexahydrobenz [cdlindole ethylene ketal and 20 ml. of ethanol is treated with a slight excess of anhydrous hydrogen chloride gas. Sufficient ether is added to the resulting solution to bring about precipitation of the -l benzoyl-5-hydroxy-5-hydroxymethyl-4-(N-methyl N acetonyl) -amino l,2,2a,3,4,5 hexahydrobenztcdJindole ethylene ketal hydrochloride which is formed in the reaction. The precipitate is removed by filtration, washed with ether, and crystallized from a mixture of ethanol and ether. "It melts with decomposition at about 230- 235 C.

. Similarly, when '1-benzoyl-5-hydroxy 5-acetoxymethyl- V .4- (N-methyl-N-acetonyl)-amino-l,2,2a,3,4,5 hexahydroclosed in 'ExampleZ, areemployed in the procedure of this example; corresponding N-acyl-S-hydroxy-S-hydroxy'methyl-4-methylacetonylamino-1,2,2a,3,4,5 hexa hydrobenz [cdlind'ole ethyleneketals' are produced. Thus there are prepared '1-acetyl-5-hydroxy-5-hydroxymethyl- 4-(N methyl-N-acetonyl)-amino-l,2,2a,3,4,5, hexahy ,drobenz[cdlindole ethylene ketal, l-phenylacetyl-S-hydroxy.-5-hydroxymethyl-4-(N-methyl-N-acetonyl) ami no-l,2,2a,3,4,5-hexahydrobenz[cdlindole ethylene ketal, 1-n-heptanoyl-5-hydroxy-S-hydroxymethyl-4-( N methyl- N-acetonyl) -amino-1,2,2a,3,4,5 hexahydrobenz [cd] in dole ethylene ketal and 1-n-valeryl-S-hydroxy-5-hydroxymethyl 4 (N methyl-N-acetonyl)-amino-l,2,2a,3,4,5- hexahydrobenz[cd]indole ethylene ketal. Acid addition salts of these compounds are' prepared in the same manner as described hereinabove. f 7

Likewise, by employingother substituted alkylamino acetone ketals disclosed in Example 3, the corresponding -1-benzoyl-5-hydroxy-5-hydroxymethyl-4-(N-ethyl N acetonyl)-amino-1,2,2a,3,4,5 hexahydrobenzEcdlindole ethylene ketal, 1benzoyl-S-hydroxy-5-hydroxymethyl-4- (-N-butyl-N-acetonyl)-amino 1,2,2a,3,4,5-hexahydrobenz- "[cdlindole ethylene ketal, 1-benzoyl-5-hydroxy-5-hydroxymethyl-4-(N-n-heptyl-N-acetonyl) amino 1,2,2a,3, 4,5-hexahydrobenz[cdlindole ethylene ketal, l-benzoyl- S-hydroxy-5-hydroxymethyl-4-(N-methyl-N acetonyl) 'amino-1,2,2a,3,4,5 hexahydrobenzlcdlindole propylene ketal, l-benzoyl S-hydroxy-5 hydroxymethyl-4-(N-isopropylN-acetonyl)-amino 1,2,2a,3,4,5 hexahydrobenz- [cdlindole diethyl 'ketal and l-benzoyl-5-hydroxy-5-hydroxylmethylt-(N-amyl N-acetonyl) amino 1,2,2a,3,4, S-hexahydrobenz[cdlindole dipropyl ketal are obtained. These substances are also converted to their acid addition salts'in'the same manner as described hereinabove.

The temperature at which the reaction is carried out can be varied'over a range of about 50 to about 150 C. Generally speaking the reaction is more rapid at the higher temperatures.

Inert organic solvents other than those described can likewise be employed, such as toluene, xylene and the like. Y i

' EXAMPLE 5 Preparation of I-benzoyl-S -ket-4-(N-methyl-N-acet- 0nyl)-amin0 1,2,2a,3,4,5 hexahydrobenzyllca']indole ethylene ketal 7 To a mixture of 0.88 g. (0.002 mol of l-benzoyl-S- hydroxy hydroxymethyl 4 (N methyl N- acetonyl) amino 1,2,2a,3,4,5 hexahydrobenzlcdlindole ethylene ketal, 0.44 g. (0.0022 mol) of sodium periodate and 10 ml. of water are added 0.2 ml. of concentrated sulfuric acid. The mixtureis shaken occasionally while standing at room temperature for about one half hour. The resulting solution is neutralized with sodium bicarbonate whereupon an amorphous precipitate of 1-benZoyl-5-keto-4;(N-methyl-N-acetonyl)amino-1,2,- 2a,3,4,5 hexahydrobenzlcdlindole ethylene ketal is formed, which is filtered ofi, washed with water, and re crystallized from the minimum amount of warm acetone. It melts at about 135-136. C.

In carrying out the oxidation procedure of this ex- 8 ample, other oxidizing agents, for example lead tetra acetate, can be used.

EXAMPLE 6 Preparation of 1-benzoyl-4,5-epoxy-5-acetoxyrnethyI LZ- 2a,3,4,5-hexahydr0benz[cd] indole Two grams of 1-benzoyl-S-hydroxymethyl-1,2,2a,3- tetrahydrobenzEcdJindole hydrate prepared according to the procedure of Example 1 were dried at about 120 C. in vacuo. The resulting amorphous product was dissolved in '10 m1. of acetic anhydride and six drops of boron fluoride etherate were added thereto. The mixture was allowed to stand at room temperature for about three days, and then was concentrated in vacuo ata' temperature below about 40 C. The residue was dissolved'in chloroform, and the chloroform solution was washed with aqueous 5 percent sodium bicarbonate solution. The chloroform solution was dried over anhydrous magnesium sulfate, and the chloroform was removed by evaporation in vacuo. The residue, consisting of 1- benzoyl 5 -'acetoxymethyl 1,2,2a,3 tetrahydrobenzicdlindole, was crystallized from a mixture of ethyl acetate and petroleum ether, and was found to melt at about a -98 C. l benzoyl-S-acetoxymethyl-1,2,2a,3-tetrahydr-obenzEcdlindole was treated with .perbenzoic acid according to. the procedure of Example 2. The 1.- benzoyl 4,5 epoxy 5 acetoxymethyl 1,2,2a,3,4,5- hexahydrobenzlcdlindole thus prepared was found to melt at about 177-179" C. a

The function of the boron trifiuorideetherate ismerely that of a catalytic agent. It can be omitted from the reaction, although the yield is then somewhat smaller, and the reaction mixture must be permitted to stand for longer periods of time, or heated to temperatures in the range of about 35-100, C.

Other :acylating agents can be employed to clfect the acylation procedure of this example. Thus, for example, propionic anhydride, butyric anhydride, valeric anhydride and thelike can be employed to produce lower acyloxy derivatives of 1-benzoyl-4,S-epoxy-5-hydroxymethyl-1,2,- 2a,3,4,5-hexahydrobenz[cdlindole Other l-acyl-S-hydroxyrnethyl-polyhydrobenz indoles, as described in Example 2, can be employed in the procedure of this example to prepare the corresponding l-acyl-S-acyloxymethyl-polyhydrohenz[cd]indoles,

EXAMPLE 7 Preparation of 1-benzoyl-4,5-epoxy-5hydroxymethyl- 1,2,2a,3,4,5-hexahydrobenz [cd] indole from I-benzoyL 4,5 epoxy 5 formyl 1,2,2a,3,4,5 hexahydrobenz- [cdlindole V EXAMPLE 8 Preparation of 1-benzoyl-4,S-epoxy-S-acetoxymethyl-1,2,- 2a,3,4,5-hexahydr0benz[cdlindole from 1-benz0yl-4,5- epoxy 5 hydroxymethyl- 1,2,2a,3,4,5 hexahydrobenz[cd]indole A solution of 3 g. or l-benzoyl-4,5-epoxy-5-hydroxys methyl-1,2,2a,3,4,5-hexahydrobenz[cd] indole in about 15 ml. of acetic anhydride is warmed gently for about sixteen hours on a water bath, and then concentrated in vacuo. The residue is dissolved in about 50 ml.yof

chloroform, and :the. chloroform solution is. washed with about ml. of saturated sodium bicarbonate solution. The chloroform solution is dried over anhydrous magnesium sulfate, and the chloroform removed by evapora tion in vacuo. The residue, consisting of l-benzoyl-S- acetoxymethyl 4,5' epoxy 1,2,2a,-3,4,5 hexahydrobenzicdlindole, melts at about 176-178" C. after recrystallization from methanol.

EXAMPLE 9 Preparation of I-benzoyl-5-hydroxy-5-hydroxymethyl-4- (N methyl N acetonyl) amino 1,2,2a,3,4,5- hexahydrobenzlcdlindole ethylene ketal from I-benzoyl 5 hydroxy 5 acetoxymethyl 4 (N methyl- N aeetonyl) amino 1,2,2a,3,4,5 hexahydrobenz- [ed] indole ethylene ketal To a solutionof .1 g. of .Lbenzoyl-S-hydroxy-S-acetoxymethyl 4- .(N methyl N.- acetonyl) amino -'1,2,- 2a,3,4,5-hexahydrobenz[cdlindole ethylene ketal. in. of a of-equalparts ofethanoland water is added. lmoleeularequivalentof sodium hydroxide. The reaction mixture is kept at room temperature for about sixteen hours whereupon .mild hydrolysis takes place removing the. .acetyl radical from the 5.-acetoxy methyl group. Thewreaction mixture is treated with ml. of

water,.and thercsulting precipitate is removed by-filtration and washed with Water. The precipitate, consisting of 1-benzoyl-S-hydroxy-S-hydroxymethyl-4-(N-methyl-N- acetonyl) amino l,2,2a,3,4,5 hexahydrobenzEcdlindole ethylene ketal, is crystallized from ethyl acetate.

Alternatively, the product of the hydrolysis is not isolated, but instead, a slight excess over the calculated molecularly equivalent amount of sodium periodate is added to the aqueous reaction mixture from hydrolysis.

The alkaline reaction mixture is then acidified by the addition of concentrated, sulfuric acid, and by following the procedure of Example 5, l-benzoyl-S-keto-4-(N-methyl- N acetonyl) amino 1,2,2a,3,4,5-hexahydrobenz[cd]indole ethylene ketal is obtained, melting at about l35-136 C. after crystallization from Warm acetone.

I claim:

1. In the process of preparing an alkylaminoacetoneketalsuhstituted 5lr eto-polyhydrobenzkdlindole having he formula RUG- l wherein R represents a radical of the group consisting of alkyl radicals having from one to eight carbon atoms, monocarbocyclic aromatic, and monocarbocyclic aromatic-substituted lower alkyl radicals, R1 represents an alkyl radical having from oneto eight carbon atoms, R2 and Rs each represent a lower alkyl radical, and when taken together, R2 and R3 represent an alkylene chain having from two to three carbon atoms, the step which comprises heating together a polyhydrobenflcdlindole epoxide represented by the formula 1' i i RQCFNJ wherein R has the same significance as hereinabove and Re're pres ents a. member of the group consisting of hy- 1% dromethyl and lower alkylcarboxyacyloxymethyl radi cal, and aketalrepresented by the formula CH3 HNR1 whereinRi Rz and R3 have the same significance as hereinabove.

2. The process step according to claim 1, wherein the polyhydrobenz[cd]indole. epoxide is represented by the formula elk-CO 0 CH2 0 and the ketal is represented by the formula (ilHr-(EH2 I R-C ON wherein R represents a radical of the group consisting .of alkyl radicals having from one to eight carbon atoms, monocarbocyclic aromatic, and monocarbocyclic aromatic-substituted lower alkyl radicals to produce a S-hydroxymethyl-acylated polyhydrobenz[cd]indole.

7. The process step according to claim 6, wherein the polyhydrobenz[cd]indole is l-benzoyl-S-formyl-1,2,2a,3- tetrahydrobenz[cd1indole.

8. In the process of preparing .an alkylaminoacetoneketal-substituted S-keto-polyhydrobenz[cd]indole, the step which comprises treating with a mild oxidizing agent a 5-hydroxymethylpolyhydrobenz[cd]indole represented by the formula RCO-N wherein R represents" a radical of the group consisting'of alkyl radicals having from one to eight carbon atoms, monecarbocyclic aromatic and monocarbocyclic aromade-substituted lower alkyl radicals to produce the corresponding 4,5-epoxy-polyhydrobenz[cd]indole.

9. The process step according to claim 8, wherein the polyhydrobenzEcdlindole is 1 benzoyl 5 hydroxymethyl-1,2,2a,3-tetrahydrobenz[cd]indole.

10. In the process of preparing an alkylaminoacetoneketal substituted 5-keto-polyhydrobenz[cdlindole, the step which comprises subjecting to the action of a carboxyacylating agent a 5-hydroxymethyl-substituted polyhydrobenz[cdlindole represented by the formula wherein R represents a radical of the group consisting of alkyl radicals having from one to eight carbon atoms, monocarbocyclic aromatic and monocarbocyclic aromatic-substituted lower alkyl radicals.

11. The process step according to claim 10, wherein the polyhydrobenzEcdlindole is 1 benzoyl 5 hydroxymethyl-1,2,2a,3 -tetrahydrobenz [cd] indole.

12. In the process of preparing an alkylaminoacetoneketal-substituted S-keto-polyhydrobenz[cd]indle, the step which comprises subjecting to the action of an epoxidizing agent a substituted polyhydrobenzcdlindole CHzOCO-alk RCO-N wherein alk represents a lower alkyl radical and R represents a radical of the group consisting of alkyl radicals having from one to eight carbon atoms, monocarbocyclic aromatic and monocarbocyclic aromatic-substituted lower alkyl radicals.

13. The process step according to claim 12 wherein the substituted po1yhydrobenz[cd]indole is 1 benzoyl acetoxymethyl-l,2,2a,3-tetrahydrobenz[cd]indole.

14. In the process of preparing an alkylaminoacetoneketal substituted 5 keto polyhydrobenzEcdJindole, the step which comprises subjecting to the action of an oxidizing agent of the group consisting of lead tetraacetate and periodic acid a polyhydrobenzkdlindole represented by the formula Rs I O HOH2G OH N-Rr ' 12 the polyhydrbbenzEcdlindole is represented by the formula alk-C ON wherein alk represents a lower alkyl radical.

16. The process step according to claim 14, wherein the polyhydrobenz[cd]indole is 1 benzoyl 4 (N- methyl N acetonyl) amino 5 hydroxy 5 hydroxymethyl 1,2,2a,3,4,5 hexahydrobenz[cd]indole ethylene ketal.

17. In the process of preparing an alkylaminoacetoneketal substituted 5 keto polyhydrobenz[cd]indole, the step which comprises subjecting to alkaline hydrolysis under mild conditions a polyhydrobenzEcdlindole represented by the formula alk-000GB: 0H

R-C ON wherein R represents a radical of the group consisting of alkyl radicals having from one to eight carbon atoms, monocarbocyclic aromatic, and monocarbocyclic aromatic-substituted lower alkyl radicals, R1 represents an alkyl radical having from one to eight carbon atoms, R2 and R3 each represent a lower alkyl radical and when taken together R2 and R3 represent an alkylene radical having from two to three carbon atoms, and alk represents a lower alkyl radical.

18. In the process for preparing an alkylaminoacetoneketal-substituted S-keto-polyhydrobenz[cd]indole, the step which comprises carboxyacylating the hydroxymethyl group of a substituted polyhydrobenzlcd] indole represented by the formula HO CH: 0

20. A compound of thegroup consisting of N-carboxy acyl derivatives of a base, the said base being represented by the formula (IJ aOH 21. l benzoyl S-hydroxymethyl-1,2,2a,3-tetrahydrobenzEcdlindole.

22. A compound selected from the group consisting of N-carboxyacyl derivatives of a base, the said base being represented by the formula HO OH:

23. 1 benzoyl-5-hydroxymethyl-4,S-epoxy-l,2,2a,3,4, S-hexahydrobenzEcd]indole.

24. A compound of the group consisting of N-carboxyacyl derivatives of a base, the said base being represented by the formula I HN alk-COOCHa 0 wherein alk represents a lower alkyl radical.

27. 1 benzoyl 5-acetoxymethyl-4,5-epoxy-1,2,2a,3,4, S-hexahydrobenzlcdlindole.

14 28. A compound of the group consisting of a base and the acid addition salts thereof, the said base being represented by the formula Boo-b wherein R represents a radical of the group consisting of aliphatic radicals having from one to eight carbon atoms, monocarbocyclic aromatic, and monocarbocyclic aromatic-substituted lower alkyl radicals, R1 represents an alkyl radical having from one to eight carbon atoms, R2 represents a member of the group consisting of hydroxymethyl and lower acyloxymethyl radicals, R3 and R4 each represent a lower alkyl radical, and when taken together, R3 and R4 represent an alkylene chain having from two to three carbon atoms.

29. 1 benzoyl 4-(N-methyl-N-acetonyl)-amino-5-hydroxy S-hydroxymethyl-1,2,2a,3,4,5-hexahydrobenz[ed]- indole ethylene ketal.

30. 1 benzoyl 4-(N-methyl-N-acetonyl)amino-5-hydroxy 5-acetoxymethyl-1,2,2a,3,4,5-hexahydrobenz[cdlindole ethylene ketal.

31. A compound of the group consisting of N-carboxyacyl derivatives of a base, the said base being represented by the formula 32. 1 benzoyl 4,5-epoxy-5-formyl-1,2,2a,3,4,5-hexahydrobenzicdlindole.

References Cited in the file of this patent Chemical Abstracts, vol. 48, page 10032 (1954), cit-' ing Helv., vol. 36, pages 1125-1142 (1953).

Jour. Am. Chem. Soc., vol. 71, page 761 (1949). 

1. IN THE PROCESS OF PREPARING AN ALKYLAMINOACETONEKETAL-SUBSTITUTED 5-KETO-POLYHYDROBENZ(CD)INDOLE HAVING THE FORMULA
 28. A COMPOUND OF THE GROUP CONSISTING OF A BASE AND THE ACID ADDITION SALTS THEREOF, THE SAID BASE BEING REPRESENTED BY THE FORMULA 